cloprostenol and sulprostone

Although prostanoids are known to be involved in regulation of the spontaneous beating rate of cultured neonatal rat cardiomyocytes, the various subtypes of prostanoid receptors have not been investigated in detail. In our experiments, prostaglandin (PG)F(2α) and prostanoid FP receptor agonists (fluprostenol, latanoprost and cloprostenol) produced a decrease in the beating rate. Two prostanoid IP receptor agonists (iloprost and beraprost) induced first a marked drop in the beating rate and then definitive abrogation of beating. In contrast, the prostanoid DP receptor agonists (PGD(2) and BW245C) and TP receptor agonists (U-46619) produced increases in the beating rate. Sulprostone (a prostanoid EP(1) and EP(3) receptor agonist) induced marked increases in the beating rate, which were suppressed by SC-19220 (a selective prostanoid EP(1) antagonist). Butaprost (a selective prostanoid EP(2) receptor agonist), misoprostol (a prostanoid EP(2) and EP(3) receptor agonist), 11-deoxy-PGE(1) (a prostanoid EP(2), EP(3) and EP(4) receptor agonist) did not alter the beating rate. Our results strongly suggest that prostanoid EP(1) receptors are involved in positive regulation of the beating rate. Prostanoid EP(1) receptor expression was confirmed by western blotting with a selective antibody. Hence, neonatal rat cardiomyocytes express both prostanoid IP and FP receptors (which negatively regulate the spontaneous beating rate) and prostanoid TP, DP(1) and EP(1) receptors (which positively regulate the spontaneous beating rate).

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Animals, Newborn; Blotting, Western; Cells, Cultured; Cloprostenol; Dibenz(b,f)(1,4)oxazepine-10(11H)-carboxylic acid, 8-chloro-, 2-acetylhydrazide; Dinoprostone; Dose-Response Relationship, Drug; Epoprostenol; Hydantoins; Iloprost; Latanoprost; Myocytes, Cardiac; Prostaglandin D2; Prostaglandins F, Synthetic; Rats; Rats, Sprague-Dawley; Receptors, Prostaglandin; Receptors, Prostaglandin E, EP1 Subtype; Receptors, Thromboxane

The aim of this study was to determine whether the magnitude of the intraocular-pressure (IOP)-lowering response in monkeys to the nonselective prostaglandin (PG)F(2a)-isopropyl ester (ie) can be reproduced by combining other PG-subtype-selective compounds. IOP was lowered by approximately 25% after 4-5 days of topical administration with latanoprost (FP agonist, 1.5 microg, q.d.), bimatoprost (prostamide, whose metabolites have been shown to be FP agonists; 9 microg, q.d.), or travoprost (FP agonist, 1.2 microg, q.d) or the EP2 agonist, butaprost (25 microg, b.i.d.). The EP1 agonist, 17-phenyl trinor (PhT) PGE2 (b.i.d.), and EP3 agonist, sulprostone (b.i.d.), had no IOP-lowering effects. The addition of butaprost, sulprostone (10 microg), or 17PhTPGE2 (25 microg) to latanoprost did not lower IOP more than latanoprost alone. However, treatment with the combination of latanoprost, 17PhTPGE2, butaprost, and sulprostone produced a similar 50-55% reduction in IOP, as did PGF(2)alpha-ie (b.i.d.). In conclusion, latanoprost, travoprost, and bimatoprost produce similar IOP-lowering responses in normotensive monkeys and are most efficacious when administered q.d. pm, compared to b.i.d. The combination of the FP, EP1, EP2, and EP3 agonists used in this study was sufficient to lower IOP by the same magnitude as PGF(2)alpha-ie, suggesting that combining PG-subtype agonists may be a potent antiglaucoma strategy.

Topics: Administration, Topical; Alprostadil; Amides; Animals; Antihypertensive Agents; Bimatoprost; Cloprostenol; Dinoprost; Dinoprostone; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; Humans; Intraocular Pressure; Latanoprost; Macaca fascicularis; Male; Ophthalmic Solutions; Prostaglandins F, Synthetic; Receptors, Prostaglandin; Receptors, Prostaglandin E; Tonometry, Ocular; Travoprost

To investigate long-term changes in the anterior segment of primate eyes treated for one year with different prostaglandin agonists and a prostamide. The results were compared with those obtained after vehicle treatment and in untreated controls.. Sixteen young cynomolgus monkeys were unilaterally topically treated for 1 year with either bimatoprost 0.03% (prostamide), sulprostone 0.03% (EP(3)/EP(1) agonist), AH13205 0.1% (EP(2) agonist), or latanoprost 0.005% (FP agonist), which all lower IOP in this species at the doses applied. Four animals were treated with the vehicle only. In all cases the left eye was treated, the right eye remained untreated. Six monkeys served as untreated controls. Sections from 4 quadrants each of the circumference of the eyes of 16 drug-treated, 4 vehicle-treated and 6 untreated control animals were investigated qualitatively and quantitatively using light- and electronmicroscopy. The area of widened spaces between ciliary muscle bundles, the number of nerve fiber bundles at the muscle tips, and the width and length of the ciliary muscle were quantitated.. The general morphology of the ciliary muscle and trabecular meshwork was normal in appearance and shape in all animals, whereas some localized morphologic changes were observed in the drug-treated animals. The changes were found to be similar in all four treatment groups. In the ciliary muscle, there was a significant increase in optically empty spaces between muscle bundles in the anterior portion of the longitudinal and the reticular ciliary muscle compared with untreated and vehicle-treated control animals. Within these spaces, significantly more myelinated nerve fiber bundles were found in drug-treated compared with normal control animals. Ultrastructurally the spaces were partly covered by endothelial-like cells which, in some areas, were in contact with the basement membrane of the microvasculature. In all treatment groups, there were also changes in the trabecular meshwork region. Significant regional differences among the different quadrants of the eyes and quantitative differences between treatment groups were observed. The ciliary epithelium had a normal appearance in all treatment groups.. After one year of treatment with different prostaglandins and a prostamide, uveoscleral outflow pathways are enlarged and appear organized. Conventional outflow routes were also affected. Long-term treatment with AH13205, latanoprost, sulprostone, or bimatoprost also induces sprouting of nerve fibers.

Topics: Administration, Topical; Amides; Animals; Anterior Eye Segment; Antihypertensive Agents; Bimatoprost; Ciliary Body; Cloprostenol; Dinoprostone; Intraocular Pressure; Latanoprost; Lipids; Macaca fascicularis; Muscle, Smooth; Nerve Fibers; Ophthalmic Solutions; Peripheral Nervous System; Prostaglandins F, Synthetic; Prostanoic Acids; Trabecular Meshwork

Cumulative concentration-effect curves for prostaglandin E(2), sulprostone and butaprost were constructed in matched strips of human non-pregnant myometrium from 14 different donors. All samples were obtained from the mid-lateral wall of the uterus. Prostaglandin E(2) produced four types of concentration-effect curves: monophasic inhibitory (n = 7), monophasic excitatory (n = 2), biphasic consisting of an excitatory phase followed by an inhibitory phase (n = 4), and biphasic consisting of an inhibitory phase followed by an excitatory phase (n = 1). Sulprostone produced excitation of spontaneous contractile activity in all tissues (mean pEC(50) = 9.1+/-0.2, range 8.1-10.1, n = 14). Butaprost produced relaxation of cloprostenol-stimulated contractile activity in all tissues (mean pEC(50) = 5.7 +/- 0.1, range 5.0-6.9, n = 14). The mean pEC(50) value for sulprostone was significantly higher in tissues where prostaglandin E(2) caused some excitation (pEC(50) = 9.4 +/- 0.2, n = 7) compared to those where prostaglandin E(2) caused only inhibition (pEC(50) = 8.8 +/- 0.2, n = 7). Mean pEC(50) values for butaprost were not significantly different between these groups. These data suggest that (a) variability in EP receptor-mediated responses exists within a single anatomical site; (b) both excitatory and inhibitory EP receptor-mediated pathways are always operative in human non-pregnant myometrium, regardless of the type of tissue response to prostaglandin E(2); and (c) regulation of EP receptor-mediated responses occurs predominantly in the excitatory (EP(3) or EP(1) receptor) pathway rather than the inhibitory (EP(2) receptor) pathway.

Topics: Adult; Alprostadil; Cloprostenol; Dinoprostone; Dose-Response Relationship, Drug; Female; Humans; In Vitro Techniques; Muscle Contraction; Myometrium